Tuesday, January 25, 2022

FDA Removes Authorization For Two Monoclonal Antibody Therapies Due To Omicron

Antigenic Diversity of SARS-CoV-2


Three weeks ago, in Preprint: Mapping the Antigenic Diversification of SARS-CoV-2, we looked at the remarkable antigenic leap that Omicron has made away from previous COVID strains (see graphic above), which likely explains the diminished effectiveness of current vaccines.

A few days earlier, in CDC HAN #00461: Using Therapeutics to Prevent and Treat COVID-19, we looked at a warning that two of the most frequently prescribed monoclonal antibody treatments (bamlanivimab and etesevimab and casirivimab and imdevimab) were no longer believed effective against Omicron.

While there is one remaining monoclonal antibody - sotrovimab - that is expected to be effective against Omicron, it is in very short supply, and its use must be strictly prioritized.  

When these announcements were made, Delta was still producing about 25% of new infections in the United States, and so these two monoclonal antibody therapies remained available (see HAN note below). 

If the Delta variant still represents a significant proportion of infections in a region and other options are not available or are contraindicated, eligible patients can be offered bamlanivimab and etesevimab or casirivimab and imdevimab, with the understanding that these treatments would be ineffective against the Omicron variant. This concern can be mitigated if virus-specific diagnostic testing a given patient indicates infection with the Omicron variant is unlikely.

But since then, Omicron has risen to roughly 99% of all cases in the country, which led the FDA yesterday to pull the plug on the use of two monoclonal antibody treatments – bamlanivimab and etesevimab (administered together) and REGEN-COV (casirivimab and imdevimab) in any U.S. state, territory, and jurisdiction  at this time.

Many hospitals around the country have already ceased using these monoclonal antibody treatments, given their lack of effectiveness against Omicron, and the FDA's announcement was not unexpected. 

There are two oral antivirals (Paxlovid and molnupiravir) still available, but Paxlovid is in very short supply while molnupiravir provides significantly less effectiveness (30% vs 88%), and has several use restrictions (including in pregnant women, women who are breastfeeding, pediatric patients, etc.).

The FDA's full announcement follows:

Coronavirus (COVID-19) Update: FDA Limits Use of Certain Monoclonal Antibodies to Treat COVID-19 Due to the Omicron Variant
The following is attributed to Patrizia Cavazzoni, M.D., director of the FDA’s Center for Drug Evaluation and Research

For Immediate Release:January 24, 2022 Statement From:Patrizia Cavazzoni, M.D.
Director - Center for Drug Evaluation and Research

As we have throughout the COVID-19 pandemic, the U.S. Food and Drug Administration has used the best available science as the virus has evolved to make informed decisions with the health and safety of the American public in mind. Ensuring that healthcare providers on the frontlines have the best tools available to treat patients is a top priority for the agency.

In light of the most recent information and data available, today, the FDA revised the authorizations for two monoclonal antibody treatments – bamlanivimab and etesevimab (administered together) and REGEN-COV (casirivimab and imdevimab) – to limit their use to only when the patient is likely to have been infected with or exposed to a variant that is susceptible to these treatments.

Because data show these treatments are highly unlikely to be active against the omicron variant, which is circulating at a very high frequency throughout the United States, these treatments are not authorized for use in any U.S. states, territories, and jurisdictions at this time. In the future, if patients in certain geographic regions are likely to be infected or exposed to a variant that is susceptible to these treatments, then use of these treatments may be authorized in these regions.

Monoclonal antibodies are laboratory-made proteins that mimic the immune system’s ability to fight off harmful pathogens such as viruses, like SARS-CoV-2. And like other infectious organisms, SARS-CoV-2 can mutate over time, resulting in certain treatments not working against certain variants such as omicron. This is the case with these two treatments for which we’re making changes today.

Based on Centers for Disease Control and Prevention data, the omicron variant of SARS-CoV-2 is estimated to account for more than 99% of cases in the United States as of Jan. 15. Therefore, it’s highly unlikely that COVID-19 patients seeking care in the U.S. at this time are infected with a variant other than omicron, and these treatments are not authorized to be used at this time. This avoids exposing patients to side effects, such as injection site reactions or allergic reactions, which can be potentially serious, from specific treatment agents that are not expected to provide benefit to patients who have been infected with or exposed to the omicron variant.

The NIH COVID-19 Treatment Guidelines Panel, an independent panel of national experts, recently recommended against the use of bamlanivimab and etesevimab (administered together) and REGEN-COV (casirivimab and imdevimab) because of markedly reduced activity against the omicron variant and because real-time testing to identify rare, non-omicron variants is not routinely available.

Importantly, there are several other therapies – Paxlovid, sotrovimab, Veklury (remdesivir), and molnupiravir – that are expected to work against the omicron variant, and that are authorized or approved to treat patients with mild-to-moderate COVID-19 who are at high risk for progression to severe disease, including hospitalization or death. Healthcare providers should consult the NIH panel’s COVID-19 treatment guidelines and assess whether these treatments are right for their patients.

While it’s critical that we have ways to treat those who contract COVID-19, the authorized treatments are not a substitute for vaccination in individuals for whom COVID-19 vaccination and a booster dose are recommended. Data has clearly demonstrated that the available, safe and effective vaccines can lower your risk of developing COVID-19 and experiencing the potential associated serious disease progression, including hospitalization and death.

The FDA is committed to continuing to review emerging data on all COVID-19 therapies related to the potential impact of variants and revise the authorizations further as appropriate to ensure healthcare providers have an effective arsenal of treatments for patients.

          (Continue . . . )


Pharmacologically, the cupboard for Omicron has grown relatively bare (at least compared to Delta), and that is a trend that could potentially accelerate as other variants emerge. 

Six months ago, in UK SAGE: Can We Predict the Limits of SARS-CoV-2 Variants and their Phenotypic Consequences?, we looked at predictions that current vaccines, and therapeutics like monoclonal antibodies, could be rendered less effective if the SARS-COV-2 virus were to drift antigenically away from earlier strains. 

Scenario Two: A variant that evades current vaccines.
This could be caused by: 
3. Antigenic ‘shift’: Natural recombination events that insert a different spike gene sequence (or partial sequence) from human CoVs MERS-CoV (highly unlikely due to the low frequency of MERS-CoV infections), or from currently circulating endemic human CoVs (more likely due to the prevalence of these viruses). This would recombine into the ‘body’ of SARS-CoV-2 that is capable of high replication in human cells. The consequence could be a virus that causes disease at a level similar to COVID-19 when it first emerged but against which our current battery of spike glycoprotein-based vaccines would not work.

Likelihood: Realistic possibility.


Scenario Three: Emergence of a drug resistant variant after anti-viral strategies. 

This could be caused by: 

6. Emergence of new variants following the administration of directly acting antiviral therapies. As we begin to use directly acting antiviral drugs it is highly likely a variant will be selected that had resistance to individual agents. For example, drugs that target the viral 3C protease, drugs that target the polymerase, monoclonal antibodies that target the spike glycoprotein. If the drugs are used as a mono therapy, then resistant variants have a high probability of emerging. This may render all drugs in that category unusable. 

Likelihood: Likely - unless the drugs are used correctly. 

It should be noted that vaccines still appear to provide significant protection against severe illness, hospitalization, and death, but their ability to prevent infection has fallen sharply.  

It is possible the next COVID variant will move antigenically closer to Delta, and breathe new life into some of these therapeutics, but so far, the virus hasn't done us very many favors.